Feng Li, Ph.D. - US grants

The broad, long-term objective is to understand how retina can adapt itself to environmental light changes to protect photoreceptor cells from degeneration and to elucidate the mechanism whereby this adaptation system is triggered, and eventually, to manipulate this system to increase photoreceptor cell resistance to the degeneration. The focus of this research proposal is to characterize the genes and protein expression as a function of retinal adaptation in response to bright cyclic light, and to understand how this adaptation protects photoreceptors from degeneration. To achieve this goal, the gene and protein expressions of bFGF, aFGF, FGF receptor-1, CNTF, CNTF receptor- alpha, BDNF, trk B, IGF-1 and IGF-1 receptor, as well as proto-oncogene bcl-2 will be quantitatively characterized by performing Northern and Western blot analysis. Afterward, in situ hybridization and immunocytochemistry will be performed to localize the expression. In addition, such adaptation system in adult rat retina triggered by bright cyclic light to protect photoreceptors from degeneration will also be examined.

This project is a collaborative effort involving Indiana University-Purdue University Indianapolis, Rochester Institute of Technology, and Tennessee State University. The investigators are taking a comprehensive approach to advance smartphone security research and education. The approach includes collaborative virtual lab design and implementation, curriculum development, faculty professional development, and partnership development.

The investigators are developing and building a Smartphone Virtual Computing Laboratory (SVCL), which caters to Computer Science, Information Technology, and Computer Engineering undergraduate and graduate students' intellectual curiosity and complements their anecdotal knowledge of mobile and cloud security. The SVCL provides an interactive and collaborative learning experience to students by allowing them to work on interesting and challenging projects derived from current research. With SVCL, students can work together, anytime, anywhere, which, in turn, helps them foster a constant learning habit that will benefit their careers. Using smartphone security as the unifying theme, the investigators are developing hands-on laboratory modules from latest research on smartphone application (app) security, smartphone operating system (OS) security, smartphone cloud security, and smartphone network security. They will also host workshops to disseminate the curriculum materials to faculty at other institutions.

Through these efforts, the project aims to expose students to latest research on smartphone and cloud computing security. The project also aims at delivering a repository of teaching/learning materials on smartphone security that allows students to learn, work, and explore together through ubiquitous access to the virtual learning and experimentation environment, SVCL. The background of the institutional collaboration (public, private, and HBCU) brings greater diversity to the pool of student participants.

This award establishes a new CISE REU site focused on mobile computing security at Indiana University Purdue University Indianapolis. A team of faculty will lead undergraduate students in hands-on projects based on the latest research on mobile device security, mobile cloud security, and mobile social network security. Working together in small groups, the students will learn how to plan, implement, and evaluate research projects. Participating students will have access to an internal cloud computing platform as well as smartphones and tablet computers. Through this program, participants will gain first-hand experience in research and graduate student life, which will help them make informed decisions in pursuing postgraduate studies as well as in choosing professional careers. This project is co-funded by the CISE Secure and Trustworthy Cyberspace (SaTC) Cluster.

Intellectual Merit. The intellectual merit of this proposal includes a faculty with expertise in mobile and cloud computing security, an important and timely area of computing that is of national interest. Students will acquire first-hand experiences with state-of-the-art technologies, which are often inaccessible to them due to high acquisition and maintenance costs. Through this REU grant, students will work with faculty mentors in completing cutting-edge research projects that have the potential to change our everyday computing experiences. By the end of program, students will acquire valuable skills, gain a broader and deeper understanding of research, and develop greater confidence in their abilities.

Broader Impact. The broader impact of this proposal is to help students tap into cutting-edge research, to boost their interests in science and engineering, and to inspire them to pursue postgraduate education in these fields. The team is committed to recruiting underrepresented minority and female students, as well as students from institutes with inadequate resources to conduct research in mobile computing security. Thus the project has the potential to produce new computer science graduate students and faculty members and to advance discovery and understanding while promoting learning.

ACM MobiHoc conference is the leading international conference on the theory and practice of mobile multi-hop wireless networks. It invites research contributions addressing the challenges in the area of multi-hop wireless networks, ranging from cognitive radio networks to ad hoc networks. The conference features a high-quality technical program, with an acceptance rate of around 10% out of around 250 submissions. It has a single-track session, which offers significant opportunities for individual and small groups that foster technical and social interactions among a diverse set of participants. MobiHoc is also an international conference that stimulates exchanges between various international research communities.

This award will help increase the representation and participation of United States-based students at the conference by providing 20 or more travel grants limited to a maximum of $750 each. By creating new opportunities for graduate students, especially those from under-represented groups, to attend a high-quality conference, this award will benefit the students by giving them an opportunity to interact with world-class researchers, inspire them to try new research directions, providing mentoring opportunities, as well as the chance to seek out internships and post-doctoral positions which will help the students advance in their research career.

This project will help address the critical need for more graduates who have a foundation in cybersecurity concepts and skills. It will utilize a cyberinfrastructure learning experience, through the use of a mobile cloud-based virtual laboratory (MCVE), to introduce cybersecurity material to computer science (CS), information technology (IT), and computer engineering (CE) students at Indiana University-Purdue University at Indianapolis (IUPUI), Rochester Institute of Technology (RIT), and Tennessee State University. Existing courses can be enhanced with the addition of relevant lab modules, and this approach will make it possible for students to see directly how computer science and engineering concepts can be used in real problem-solving. This project will promote recruitment and retention of CS, CE, and IT students for careers in cybersecurity. In addition, a number of professional development and outreach workshops will help increase the number of university faculty prepared to offer courses that utilize the same underlying system, and also prepare high school teachers to, at minimum, make students aware of cybersecurity issues and practices.

The educational activities involved in this project will use the RISE (Research, Interactive, Service, and Experiential) learning components in order to teach cybersecurity concepts and skills. The learning components will utilize MCVE as the mechanism for delivering the RISE laboratory modules. The MCVE infrastructure is based on smartphones and cloud computing resources that are available at the three universities and through the Amazon EC2 system. The cloud security testbed at IUPUI and the RIT computation grid will be used to create virtual machines and network topologies on which security experiments can be conducted. The TSU Cloud at Tennessee State will be used to serve a malware database. Finally, the Amazon Web Services can be used for security implementation experiments. This collection of resources will allow students who work with the MCVE to experiment with a range of system, network, and cloud configurations. Students will have the opportunity to work with MCVE through numerous courses that span the CS, IT, and CE curricula, addressing secure programming, cryptography, security architecture, network security, and security policy. Project evaluation will be done with a mixed methods approach, specifically focusing on the skills and increased competency students gain as a result of the RISE lab modules, change in student understanding of the connection between cybersecurity concepts and techniques, changes in recruitment and retention of CS, CE, and IT students. Evaluation will include student surveys, learning outcome measures, instructor interviews, and classroom observations. This project will be funded by the Division of Undergraduate Education, through the IUSE program, and the Division of Graduate Education, through the SFS program.

This CISE Research Experiences for Undergraduates (REU) Site award funds the renewal of an outstanding REU site at Indiana University - Purdue University Indianapolis. The site will recruit undergraduates from across the nation to participate in research topics related to mobile cloud security, which focuses on issues related to the use of mobile devices such as smart phones and the secure use of mobile clouds to access, manage, store, and secure digital assets. Mobile cloud security is an area of current interest that is well-suited to undergraduate research productivity. The students will use controlled and competitive test environments to experiment with cyber attack and defense techniques needed to secure the mobile devices that are pervasive in our society. This site should help develop a group of computing professionals who can develop the systems of the future that impact society and enhance our quality of life. The REU experience provides students with the foundations and inspiration to pursue computing careers and research in areas that are rapidly evolving and impacting all of our citizens. This site is co-funded by the Secure and Trustworthy Cyberspace program.

The is project is led by an outstanding team offering state-of-the art facilities and professional mentors to guide undergraduates in explorations of problems related to mobile cloud security. Students will learn how to use current tools and techniques to solve those problems that have direct impact on people. The team will use proven strategies to recruit undergraduate students from groups traditionally under-represented in computer science including African American, Hispanic and female students. The students will participate in research and professional development activities all designed to achieve the goals of retaining and graduating undergraduate students in computer science and engineering, recruiting students from groups traditionally under-represented in computing fields, and increasing recruitment of students into graduate programs.

Project Summary/Abstract: Liquid biopsy (LB) is the analysis of cell-free circulating tumor DNA (ctDNA) in readily-accessible body fluids to non-invasively profile the molecular landscape of solid tumors. Liquid biopsy based on ctDNA can be used to detect actionable mutations, monitor response to treatments and assess the emergence of drug resistance. Liquid biopsy is particularly attractive in non-small cell lung cancer (NSCLC) as activating mutations in Epidermal Growth Factor Receptor (EGFR) confer sensitivity to Tyrosine Kinase Inhibitors(1). However, the analytical sensitivity for liquid biopsy technologies for detecting ctDNA and associated genomic changes is limited by its low concentration compared to cell-free DNA (cfDNA) of non-tumor origin. In 2016, FDA approved the Cobas EGFR Mutation Test v2 using plasma as the first liquid biopsy test for diagnostic use. However, the reported sensitivity for the detection of the 2 most common activating mutations (exon 19 deletions or exon 21 substitutions) in the EGFR gene is only 76.7%(2). Improving the sensitivity of mutation detection could further unlock the potential of liquid biopsies for the diagnosis of cancer including earlier stage detection as well as detection of minimal residual disease. Liquid biopsy analytical platforms that deliver detection sensitivity closest to tissue biopsy-based genotyping of tumor-specific ctDNA is an unmet clinical need. Our preliminary study showed the existence of a novel group of ultrashort circulating tumor DNA (uctDNA) molecules with EGFR mutations in plasma samples from non-small cell lung cancer (NSCLC) patients. This NCI Clinical and Translational Exploratory/Developmental Studies R21 application is to explore and test our hypothesis that there are abundant uctDNA molecules in blood and saliva samples from NSCLC and these uctDNA fragments are additional circulating tumor targets that will improve the sensitivity of liquid biopsy. Two specific aims are in place for hypothesis testing. Aim 1 is to recruit, enroll 250 NSCLC patients that from UCLA Medical Center (UCLAMC) Pulmonary Disease Clinic and VA Greater Los Angeles (VA GLA) Pulmonary Disease Clinic. Plasma will be collected from each patient. Aim 2 is to validate clinical utility of uctDNA NGS assay targeting uctDNA for liquid biopsy of NSCLC. Together, the translational and clinical validations, targeting uctDNA for liquid biopsy can break new ground and extend previous discoveries towards impactful new directions and clinical applications.

ABSTRACT Anti-depressant drug-induced liver injury is a major clinical concern, with up to 3% of patients treated showing evidence of liver damage. Duloxetine (DLX), the first-line and most prescribed antidepressant, carries a black box warning for its hepatotoxicity, but the mechanisms of DLX-induced liver injury remain largely unknown. Based on our preliminary data and clinical evidence, we hypothesize that DLX causes liver damage by disrupting hepatic lysophosphatidylcholine (LPC) homeostasis, and that suppression of DLX metabolism increases LPC accumulation and potentiates hepatotoxicity. The goal of this application is to determine the mechanism(s) of DLX-induced liver injury to enable the prediction and prevention of DLX hepatotoxicity. We will pursue this goal through three specific aims: (1) To determine if modifying LPC homeostasis impacts DLX toxicity, we will block LPC production pharmacologically with phospholipase A2 inhibitors and partially block LPC consumption genetically with Lpcat3-/- mice. We will determine DLX toxicity and assess LPC levels in the liver and blood. (2) To determine the mechanism by which DLX causes accumulation of LPCs, we will test whether DLX inhibits lysophospholipase, the enzyme that degrades LPC. We will test the mechanistic effect of DLX on lysophospholipase in vitro and in vivo using stable-isotope LPCs and known inhibitors. (3) We will use Cyp1a2-/-, Cyp2d-/-, or L-Porc/c mouse models to block CYP-mediated DLX metabolism and determine how this influences LPC levels and potentiates hepatotoxicity. We will use our novel human liver chimeric mice, in which mouse hepatic P450 oxidoreductase is non-functional, to assess Phase I metabolism of DLX and determine how inhibitors for specific human P450s impact hepatotoxicity of DLX. Completion of the proposed studies should help us understand the underlying mechanisms of DLX hepatotoxicity and provide an explanation for clinically observed DLX-drug interactions. Our research strategies could provide a general approach for the toxicological community to investigate drug-induced liver injury. These findings may lead to novel strategies for prediction and prevention of DLX hepatotoxicity in clinic and improvement of the DLX clinical safety profile.

ABSTRACT Developing a small molecule male contraceptive is complicated by the blood-testis barrier (BTB) and blood- epididymal barrier (BEB), since many male contraceptive targets are localized to the adluminal compartment of the seminiferous epithelium or to sperm within the epididymal tubule lumen. Improved understanding of the chemical features that confer the ability for xenobiotics to cross BTB or BEB will facilitate the discovery and development of new male contraceptives. Published data and our studies of novel bromodomain testis (BRDT) inhibitors suggest that it is possible to identify properties that facilitate passage across the BTB or BEB. We will identify key chemical features that facilitate the passage of drugs across BTB and BEB in two separate R61 and R33 phases. In the R61 phase, we will 1) optimize the protocols and throughput for measuring mouse tissue distribution using a drug test set; and 2) measure tissue distribution of 100 compounds and their metabolites and identify molecular descriptors that influence delivery to the testis. We will quantify chemically unrelated compounds in mouse plasma, rete testis fluid (RTF), testis, and epididymis using liquid chromatography mass spectrometry (LC-MS). Compound spatial distribution in the rete testis, testis, and epididymis will be mapped using imaging MS. We will use chemoinformatics to correlate structures and molecular descriptors with the experimental RTF/plasma, testis/plasma, and epididymis/plasma ratios to identify features that facilitate or impede testis accumulation. In the R33 phase we plan to broaden our understanding and directly test the effects of altering the key inferred physical properties or molecular descriptors. We will 3) validate identified chemical features using a series of rationally designed synthetic analogs. Analyzing compound series will allow us to distinguish between trends in physicochemical parameters and special properties conferred by a particular chemotype. We will 4) test an additional 200 novel small molecules to identify new chemotypes that influence testis uptake and 5) test outlier compounds whose uptake belies their physical properties using transporter knock-out mice, to determine the tissue distribution that occurs without transporters so as to improve our physicochemical permeability models for the BTB and BEB. This work will establish predictive uptake rules applicable to drugs that must act behind BTB or BEB, facilitating the identification of new male contraceptives and of therapeutics for which accumulation in the immune- privileged compartments of the testis or epididymis would be beneficial.